14-95124415-T-C

Variant names:

• chr14-95124415-T-C
• rs777556655
• NM_177438.3:c.1157A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BS2_Supporting BP4 BP2

This summary comes from the ClinGen Evidence Repository: The NM_177438.3:c.1157A>G variant in DICER1 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 386 (p.Lys386Arg). This variant has been observed in trans with the variant c.3091C>T, p.Gln1031Ter (Internal lab contributors) which would be classified as pathogenic/likely pathogenic by the ClinGen DICER1 VCEP specifications (BP2). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.00001053 (17/1614068 alleles) with a highest population minor allele frequency of 0.00001356 (16/1180004 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.123; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_supporting, BP2, BP4. (Bayesian Points: -3; VCEP specifications version 1.3.0; 08/27/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA7331519/MONDO:0100216/024

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:2
• Conservation: PhyloP100: 7.45
• Publications: 1 publications found

Genes affected

DICER1 (HGNC:17098): (dicer 1, ribonuclease III) This gene encodes a protein possessing an RNA helicase motif containing a DEXH box in its amino terminus and an RNA motif in the carboxy terminus. The encoded protein functions as a ribonuclease and is required by the RNA interference and small temporal RNA (stRNA) pathways to produce the active small RNA component that represses gene expression. This protein also acts as a strong antiviral agent with activity against RNA viruses, including the Zika and SARS-CoV-2 viruses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2021]

DICER1 Gene-Disease associations (from GenCC):

• DICER1-related tumor predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pleuropulmonary blastoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• DICER1 syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.1157A>G	p.Lys386Arg	missense	Exon 8 of 27	NP_803187.1
	DICER1	NM_001271282.3		c.1157A>G	p.Lys386Arg	missense	Exon 8 of 27	NP_001258211.1
	DICER1	NM_001291628.2		c.1157A>G	p.Lys386Arg	missense	Exon 8 of 27	NP_001278557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.1157A>G	p.Lys386Arg	missense	Exon 8 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.1157A>G	p.Lys386Arg	missense	Exon 10 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.1157A>G	p.Lys386Arg	missense	Exon 8 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251374 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461828 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	DICER1-related tumor predisposition (2)
-	1	-	Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		7.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.12
Sift	Benign	0.51	T
Sift4G	Benign	0.63	T
Polyphen		0.49	P
Vest4		0.26
MutPred		0.29		Loss of methylation at K386 (P = 0.0288)
MVP		0.62
MPC		0.55
ClinPred		0.27	T
GERP RS		5.5
Varity_R		0.14
gMVP		0.33
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs777556655; hg19: chr14-95590752;